Novel thioxanthine derivatives for use as inhibitors of mpo

ABSTRACT

There are disclosed novel compounds of formula (Ia) or (Ib)  
                 
 
wherein R 1 , R 2 , R 3 , R 4 , X and Y are as defined in the specification, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of the enzyme MPO and are thereby particularly useful in the treatment or prophylaxis of neuroinflammatory disorders.

FIELD OF THE INVENTION

The present invention relates to novel thioxanthine derivatives,processes for their preparation, compositions containing them and theiruse in therapy.

BACKGROUND OF THE INVENTION

Myeloperoxidase (MPO) is a heme-containing enzyme found predominantly inpolymorphonuclear leukocytes (PMNs). MPO is one member of a diverseprotein family of mammalian peroxidases that also includes eosinophilperoxidase, thyroid peroxidase, salivary peroxidase, lactoperoxidase,prostaglandin H synthase, and others. The mature enzyme is a dimer ofidentical halves. Each half molecule contains a covalently bound hemethat exhibits unusual spectral properties responsible for thecharacteristic green colour of MPO. Cleavage of the disulphide bridgelinking the two halves of MPO yields the hemi-enzyme that exhibitsspectral and catalytic properties indistinguishable from those of theintact enzyme. The enzyme uses hydrogen peroxide to oxidize chloride tohypochlorous acid. Other halides and pseudohalides (like thiocyanate)are also physiological substrates to MPO.

PMNs are of particular importance for combating infections. These cellscontain MPO, with well documented microbicidal action. PMNs actnon-specifically by phagocytosis to engulf microorganisms, incorporatethem into vacuoles, termed phagosomes, which fuse with granulescontaining myeloperoxidase to form phagolysosomes. In phagolysosomes theenzymatic activity of the myeloperoxidase leads to the formation ofhypochlorous acid, a potent bactericidal compound. Hypochlorous acid isoxidizing in itself, and reacts most avidly with thiols and thioethers,but also converts amines into chloramines, and chlorinates aromaticamino acids. Macrophages are large phagocytic cells which, like PMNs,are capable of phagocytosing microorganisms. Macrophages can generatehydrogen peroxide and upon activation also produce myeloperoxidase. MPOand hydrogen peroxide can also be released to the outside of the cellswhere the reaction with chloride can induce damage to adjacent tissue.

Linkage of myeloperoxidase activity to disease has been implicated inneurological diseases with a neuroinflammatory response includingmultiple sclerosis, Alzheimer's disease, Parkinson's disease and strokeas well as other inflammatory diseases or conditions like asthma,chronic obstructive pulmonary disease, cystic fibrosis, atherosclerosis,inflammatory bowel disease, renal glomerular damage and rheumatoidarthritis. Lung cancer has also been suggested to be associated withhigh MPO levels.

The present invention discloses novel thioxanthine derivatives thatsurprisingly display useful properties as inhibitors of the enzyme MPO.

DISCLOSURE OF THE INVENTION

The present invention provides a compound of formula (Ia) or (Ib)

wherein:

one of X and Y represents S, and the other represents O or S;

R¹ represents hydrogen or C1 to 6 alkyl;

R² represents hydrogen or C1 to 6 alkyl; said alkyl group beingoptionally substituted by:

i) a saturated or partially unsaturated 3- to 7-membered ring optionallyincorporating one or two heteroatoms selected independently from O, Nand S, and optionally incorporating a carbonyl group; said ring beingoptionally substituted by one or more substituents selected fromhalogen, hydroxy, C1 to 6 alkoxy and C1 to 6 alkyl; said alkyl beingoptionally further substituted by hydroxy or C1 to 6 alkoxy; or

ii) C1 to 6 alkoxy; or

iii) an aromatic ring selected from phenyl, furyl or thienyl; saidaromatic ring being optionally further substituted by halogen, C1 to 6alkyl or C1 to 6 alkoxy;

R³ represents hydrogen or C1 to 6 alkyl;

R⁴ represents halogen, C1 to 6 alkyl substituted by one or more halogenatoms, C1 to 6 alkoxy or C1 to 6 thioalkoxy; said alkoxy or thioalkoxygroup being optionally further substituted by halogen or OH;

and pharmaceutically acceptable salts thereof.

The compounds of formula (Ia) or (Ib) may exist in enantiomeric forms.It is to be understood that all enantiomers, diastereomers, racematesand mixtures thereof are included within the scope of the invention.

It will be appreciated that when R³ in formulae (Ia) and (Ib) representshydrogen, the two alternative representations (Ia) and (Ib) aretautomeric forms of the same compound. All such tautomers and mixturesof tautomers are included within the scope of the present invention.

Unless otherwise indicated, the term “C1 to 6 alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1 to 6carbon atoms. Examples of such groups include methyl, ethyl, 1-propyl,n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.

The term “C1 to 4 alkyl” is to be interpreted analogously.

Unless otherwise indicated, the term “C3 to 7 cycloalkyl” referred toherein denotes a cyclic alkyl group having from 3 to 7 carbon atoms.Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.

Unless otherwise indicated, the term “C1 to 6 alkoxy” referred to hereindenotes a straight or branched chain alkoxy group having from 1 to 6carbon atoms. Examples of such groups include methoxy, ethoxy,1-propoxy, 2-propoxy and tert-butoxy.

The term “C1 to 4 alkoxy” is to be interpreted analogously.

Unless otherwise indicated, the term “C1 to 6 thioalkoxy” referred toherein denotes a straight or branched chain alkyl group having from 1 to6 carbon atoms bonded to a sulphur atom. Examples of such groups includemethylthio, ethylthio, 1-propylthio, 2-propylthio and tert-butylthio.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluoro, chloro, bromo and iodo.

Examples of a saturated or partially unsaturated 3- to 7-membered ringoptionally incorporating one or two heteroatoms selected independentlyfrom O, N and S, and optionally incorporating a carbonyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclopentanone, tetrahydrofuran,pyrrolidine, piperidine, morpholine, piperazine, pyrrolidinone andpiperidinone. Particular examples include cyclopropyl, cyclohexyl,tetrahydrofuranyl(tetrahydrofuryl) and morpholinyl.

Examples of a C1 to 6 alkyl substituted by one or more halogen atomsinclude chloromethyl, 2,2,2-trichloroethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, pentafluoroethyl and 3,3,3-trifluoropropyl.

In one embodiment, the invention relates to compounds of formula (Ia) or(Ib) wherein X represents S and Y represents O.

In another embodiment, R³ in formula (Ia) or (Ib) represents hydrogen.

In another embodiment, R² in formula (Ia) or (Ib) represents optionallysubstituted C1 to 6 alkyl.

In another embodiment, R² in formula (Ia) or (Ib) represents C1 to 6alkyl substituted by a saturated or partially unsaturated 3- to7-membered ring optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said ring being optionally substituted by one or moresubstituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6alkyl; said alkyl being optionally further substituted by hydroxy or C1to 6 alkoxy.

In another embodiment, R² in formula (Ia) or (Ib) represents methylene,ethylene or trimethylene substituted by cyclopropyl, cyclohexyl,tetrahydrofuranyl or morpholinyl.

In another embodiment, R² in formula (Ia) or (Ib) represents C1 to 6alkyl substituted by C1 to 6 alkoxy.

In another embodiment, R² in formula (Ia) or (Ib) represents ethylene ortrimethylene substituted by methoxy or ethoxy.

In another embodiment, R² in formula (Ia) or (Ib) represents C1 to 6alkyl substituted by optionally substituted phenyl, furyl or thienyl.

In another embodiment, R⁴ in formula (Ia) or (Ib) represents C1 to 6alkyl substituted by one or more halogen atoms. In another embodiment,R² in formula (Ia) or (Ib) represents C1 to 6 alkyl substituted by oneor more fluoro atoms.

When X represents S and Y represents O, a further embodiment comprisescompounds of formula (Ia) or (Ib) wherein R¹ represents hydrogen.

When X represents O and Y represents S, a further embodiment comprisescompounds of formula (Ia) or (Ib) wherein R¹ represents C1 to 6 alkyl.

In one embodiment, there are provided compounds of formula (Ia) or (Ib)wherein at least one of X and Y represents S, and the other represents Oor S; R¹ represents hydrogen or C1 to 6 alkyl; R² represents hydrogen orC1 to 6 alkyl; said alkyl group being optionally substituted by C3 to 7cycloalkyl, C1 to 4 alkoxy, or an aromatic ring selected from phenyl,furyl or thienyl; said aromatic ring being optionally furthersubstituted by halogen, C1 to 4 alkyl or C1 to 4 alkoxy; R³ representshydrogen or C1 to 6 alkyl; and pharmaceutically acceptable saltsthereof.

In another embodiment, there are provided compounds of formula (Ia) or(Ib) wherein at least one of X and Y represents S, and the otherrepresents O or S; R¹ represents hydrogen or C1 to 6 alkyl; R²represents hydrogen or C1 to 6 alkyl; said alkyl group being optionallysubstituted by: i) a saturated or partially unsaturated 3- to 7-memberedring optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said ring being optionally substituted by one or moresubstituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6alkyl; said alkyl being optionally further substituted by hydroxy or C1to 4 alkoxy; or ii) C1 to 4 alkoxy; or iii) an aromatic ring selectedfrom phenyl, furyl or thienyl; said aromatic ring being optionallyfurther substituted by halogen, C1 to 4 alkyl or C1 to 4 alkoxy; R³represents hydrogen or C1 to 6 alkyl; and pharmaceutically acceptablesalt thereof.

In one embodiment, the invention relates to compounds of formula (Ia) or(Ib) wherein X represents S and Y represents O; R² represents optionallysubstituted C1 to 6 alkyl; and R¹ and R³ each represent hydrogen.

In one embodiment, the invention relates to compounds of formula (Ia) or(Ib) wherein X represents S and Y represents O; R² represents C1 to 6alkyl substituted by a saturated or partially unsaturated 3- to7-membered ring optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said ring being optionally substituted by one or moresubstituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6alkyl; said alkyl being optionally further substituted by hydroxy or C1to 6 alkoxy; and R¹ and R³ each represent hydrogen.

In one embodiment, the invention relates to compounds of formula (Ia) or(Ib) wherein X represents S and Y represents O; R² represents C1 to 6alkyl substituted by C1 to 6 alkoxy; and R¹ and R³ each representhydrogen.

Particular compounds of the invention include:

3-isobutyl-2-thioxo-8-trifluoromethyl-1,2,3,7-tetrahydro-purin-6-one;

and pharmaceutically acceptable salts thereof.

A further aspect of the invention is the use of the novel compounds offormula (Ia) or (Ib) as a medicament.

A further aspect of the invention is the use of a compound of formula(Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofdiseases or conditions in which inhibition of the enzyme MPO isbeneficial.

A more particular aspect of the invention provides the use of a compoundof formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament, for the treatment or prophylaxis ofneuroinflammatory disorders.

Another more particular aspect of the invention provides the use of acompound of formula (Ia) or (Ib), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament, for the treatment orprophylaxis of multiple sclerosis.

According to the invention, there is also provided a method of treating,or reducing the risk of, diseases or conditions in which inhibition ofthe enzyme MPO is beneficial which comprises administering to a personsuffering from or at risk of, said disease or condition, atherapeutically effective amount of a compound of formula (Ia) or (Ib),or a pharmaceutically acceptable salt thereof.

More particularly, there is also provided a method of treating, orreducing the risk of, neuroinflammatory disorders in a person sufferingfrom or at risk of, said disease or condition, wherein the methodcomprises administering to the person a therapeutically effective amountof a compound of formula (Ia) or (Ib), or a pharmaceutically acceptablesalt thereof.

In another aspect the invention provides a pharmaceutical formulationcomprising a therapeutically effective amount of a compound of formula(Ia) or (Ib), or a pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier, for use in the treatment or prophylaxis of diseases orconditions in which inhibition of the enzyme MPO is beneficial.

In another more particular aspect the invention provides apharmaceutical formulation comprising a therapeutically effective amountof a compound of formula (Ia) or (Ib), or a pharmaceutically acceptablesalt thereof, in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier, for use in the treatment or prophylaxis ofneuroinflammatory disorders.

According to the invention, we further provide a process for thepreparation of the novel compounds of formula (Ia) or (Ib), or apharmaceutically acceptable salt, enantiomer, diastereomer or racematethereof which comprises:

(a) reaction of a compound of formula (IIa) or (IIb)

wherein R¹, R², R³ and R⁴ are as defined in formula (Ia) or (Ib), Xrepresents O or S and Y represents O;

with a sulphurising compound such as Lawesson's reagent or phosphoruspentasulphide; to give a corresponding compound wherein Y represents S;or

(b) reaction of a diamine of formula (IIIa) or (IIIb)

wherein R¹, R², R³, X and Y are as defined in formula (Ia) or (Ib);

with a trialkylorthoester or with an alpha-halo-substituted carboxylicacid or anhydride;

and where necessary converting the resultant compound of formula (Ia) or(Ib), or another salt thereof, into a pharmaceutically acceptable saltthereof; or converting the resultant compound of formula (Ia) or (Ib)into a further compound of formula (Ia) or (Ib); and where desiredconverting the resultant compound of formula (Ia) or (Ib) into anoptical isomer thereof.

In process (a), a compound of formula (IIa) or (IIb) and a sulfurisingagent such as Lawesson's reagent, or phosphorus pentasulfide aredissolved or suspended in a suitable dry organic solvent such asbenzene, toluene, xylene, tetrahydrofuran, dichloromethane or dioxaneand then heated to between 30° C. and the reflux temperature of thesolvent until reaction is complete, typically for between one to 30hours. The reaction mixture is then cooled and filtered to removeinsoluble solids. The solvent is removed under reduced pressure and thecrude product is purified by column chromatography or byrecrystallisation.

In process (b), a diamine of formula (IIIa) or (IIIb) is treated at asuitable temperature with an excess of an appropriate ortho ester suchas triethylorthoformate, triethylorthoacetate, triethylorthopropionate,triethylorthobutanoate, tripropylorthoformate, tributylorthoformate andtriisopropylorthoformate, optionally in the presence of a suitablesolvent such as an alcohol, until reaction is complete. The temperatureis typically up to the reflux temperature of the reaction mixture, andreaction times are generally from 30 minutes to overnight. In oneembodiment, the orthoester is triethylorthoformate with ethanol as anoptional solvent.

Alternatively in process (b), a diamine of formula (IIIa) or (IIIb) istreated with an alpha-halo-substituted carboxylic acid or anhydride suchas trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid,trifluoroacetic anhydride and difluoroacetic anhydride at a suitabletemperature between ambient temperature and the reflux temperature ofthe reaction mixture or in a microwave oven. The process is continuedfor a suitable period of time, typically for between 0.5 to 5 hours, or0.1-10 minutes in a microwave oven. After removal of the carboxylic acidor anhydride, treatment with a suitable aqueous base, for example, with1% or 10% aqueous sodium hydroxide solution, then yields the compound offormula (I). The treatment with base is carried out for a suitable timeat a suitable temperature, for example, for about 10 minutes to 4 hoursat a temperature between ambient temperature and the reflux temperatureof the reaction mixture.

Other methods for the conversion of a diamine of formula (IIIa) or(IIIb) into a compound of formula (Ia) or (Ib) are described in theliterature and will be readily known to the person skilled in the art.

The present invention includes compounds of formula (Ia) or (Ib) in theform of salts, in particular acid addition salts. Suitable salts includethose formed with both organic and inorganic acids. Such acid additionsalts will normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

Salts of compounds of formula (Ia) or (Ib) may be formed by reacting thefree base, or a salt, enantiomer or racemate thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, for example, water, dioxan, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuo or by freeze drying. The reaction may also be ametathetical process or it may be carried out on an ion exchange resin.

Compounds of formulae (IIa) or (IIb) and compounds of formula (IIIa) or(IIIb) are either known in the literature or may be prepared using knownmethods that will be readily apparent to the man skilled in the art.

The compounds of the invention and intermediates thereto may be isolatedfrom their reaction mixtures and, if necessary further purified, byusing standard techniques.

The compounds of formula (Ia) or (Ib) may exist in enantiomeric forms.Therefore, all enantiomers, diastereomers, racemates and mixturesthereof are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, for example, fractionalcrystallisation, or HPLC. Alternatively, the various optical isomers maybe prepared directly using optically active starting materials.

Intermediate compounds may also exist in enantiomeric forms and may beused as purified enantiomers, diastereomers, racemates or mixtures.

The compounds of formula (Ia) or (Ib), and their pharmaceuticallyacceptable salts are useful because they possess pharmacologicalactivity as inhibitors of the enzyme MPO.

The compounds of formulae (Ia) and (Ib) and their pharmaceuticallyacceptable salts are indicated for use in the treatment or prophylaxisof diseases or conditions in which modulation of the activity of theenzyme myeloperoxidase (MPO) is desirable. In particular, linkage of MPOactivity to disease has been implicated in neuroinflammatory diseases.Therefore the compounds of the present invention are particularlyindicated for use in the treatment of neuroinflammatory conditions ordisorders in mammals including man. Such conditions or disorders will bereadily apparent to the man skilled in the art.

Conditions or disorders that may be specifically mentioned includemultiple sclerosis, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis and stroke, as well as other inflammatorydiseases or conditions such as asthma, chronic obstructive pulmonarydisease, cystic fibrosis, idiopathic pulmonary fibrosis, acuterespiratory distress syndrome, sinusitis, rhinitis, psoriasis,dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory boweldisease, renal glomerular damage, liver fibrosis, sepsis, proctitis,rheumatoid arthritis, and inflammation associated with reperfusioninjury, spinal cord injury and tissuedamage/scarring/adhesion/rejection. Lung cancer has also been suggestedto be associated with high MPO levels. The compounds are also expectedto be useful in the treatment of pain.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

For the above mentioned therapeutic indications, the dosage administeredwill, of course, vary with the compound employed, the mode ofadministration and the treatment desired. However, in general,satisfactory results are obtained when the compounds are administered ata dosage of the solid form of between 1 mg and 2000 mg per day.

The compounds of formulae (Ia) or (Ib), and pharmaceutically acceptablederivatives thereof, may be used on their own, or in the form ofappropriate pharmaceutical compositions in which the compound orderivative is in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier. Thus, another aspect of the invention concerns apharmaceutical composition comprising a novel compound of formula (Ia)or (Ib), or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier.Administration may be by, but is not limited to, enteral (includingoral, sublingual or rectal), intranasal, inhalation, intravenous,topical or other parenteral routes. Conventional procedures for theselection and preparation of suitable pharmaceutical formulations aredescribed in, for example, “Pharmaceuticals—The Science of Dosage FormDesigns”, M. E. Aulton, Churchill Livingstone, 1988. The pharmaceuticalcomposition preferably comprises less than 80% and more preferably lessthan 50% of a compound of formulae (Ia) or (Ib), or a pharmaceuticallyacceptable salt thereof.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

The invention is illustrated, but in no way limited, by the followingexample:

¹H and ¹³C NMR spectra were recorded either on a 300 MHz Bruker DPXinstrument or on a Varian Unity 400 MHz spectrometer at 25° C. Thefollowing reference signals were used: the middle line of DMSO-d₆ δ39.5(¹³C); DMSO-d₆ δ2.49 (¹H). All mass spectra were recorded on a WatersLCMS (2790) instrument. Thin layer chromatography (TLC) was performed onMerck TLC aluminium sheets silica gel 60 F₂₅₄ pre-coated sheets (layerthickness 0.2 mm). Merck Silica gel 60 (0.063-0.200 mm) was used forcolumn chromatography. HPLC analysis were performed on a Agilent 1100series. Column; Waters X-Terra, C8, 3.5 μm, 4.6×100 mm. Preparativeliquid chromatography was performed on a Gilson Auto purificationsystem, gradient pump with a Gynkotek UVD 170S UV-vis detector. Column;Kromasil, C8, 10 μm, 20×250 mm. The microwave oven used is a SmithCreator, Personal Chemistry.

EXAMPLE 13-Isobutyl-2-thioxo-8-trifluoromethyl-1,2,3,7-tetrahydro-purin-6-one

5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.15 g,0.70 mmol) was suspended in trifluoroacetic acid (3.0 mL) and thissolution was heated at 100° C. for 1.5 min in a microwave oven. Excesstrifluoroacetic acid was evaporated off under reduced pressure. 0.2MSodium hydroxide (3.0 mL) was added to the orange solid and theresulting solution was heated at 100° C. for 1.5 minutes in a microwaveoven. The pH of the solution was adjusted to pH 6 with dilutehydrochloric acid. The resulting slurry was stirred for 10 min atambient temperature, then the precipitate was collected by filtrationand washed with water. Yield: (0.60 g, 29%).

¹H NMR (400 MHz, DMSO-D6) δ 12.51 (s, 1H), 4.28 (d, J=7.33 Hz, 2H), 2.47(m, 1H), 0.89 (s, 6H);

¹³C NMR (101 MHz, DMSO-D6) δ 174.51, 152.87, 148.86, 138.47, 118.27,113.77, 54.22, 26.06, 19.69 (s, 2C);

MS (LC-MS)m/z 291 (M−1).

Screens

Methods for the determination of MPO inhibitory activity are disclosedin co-pending patent application WO 02/090575. The pharmacologicalactivity of compounds according to the invention was tested in thefollowing screen:

Assay buffer: 20 mM sodium/potassium phosphate buffer pH 6.5 containing10 mM taurine and 100 mM NaCl.

Developing reagent: 2 mM 3,3′,5,5′-tetramethylbenzidine (TMB), 200 μMKI, 200 mM acetate buffer pH 5.4 with 20% DMF.

To 10 μl of diluted compounds in assay buffer, 40 μl of human MPO (finalconcentration 2.5 nM) was added for 10 minutes at room temperature. Then50 μl of H₂O₂ (final concentration 100 μM), or assay buffer alone as acontrol, were added for 10 minutes at room temperature. The reaction wasstopped by adding 10 μl 0.2 mg/ml of catalase (final concentration 18μg/ml) for 5 minutes before 100 μl of TMB developing reagent was added(2 mM TMB in 200 mM acetate buffer pH 5.4 containing 20%dimethylformamide (DMF) and 200 μM KI). Plates were mixed and the amountof oxidised 3,3′,5,5′-tetramethylbenzidine formed was then measuredafter about 5 minutes using absorbance spectroscopy at about 650 nM.IC₅₀ values were then determined using standard procedures.

When tested in the above screen, the compound of Example 1 gave an IC₅₀value of less than 60 μM, indicating that it is expected to show usefultherapeutic activity.

1-10. (canceled)
 11. A compound of formula (Ia) or (Ib)

wherein: one of X and Y represents S, and the other represents O or S;R¹ represents hydrogen or C1 to 6 alkyl; R² represents hydrogen or C1 to6 alkyl; said alkyl group being optionally substituted by: i) asaturated or partially unsaturated 3- to 7-membered ring optionallyincorporating one or two heteroatoms selected independently from O, Nand S, and optionally incorporating a carbonyl group; said ring beingoptionally substituted by one or more substituents selected fromhalogen, hydroxy, C1 to 6 alkoxy and C1 to 6 alkyl; said alkyl beingoptionally further substituted by hydroxy or C1 to 6 alkoxy; or ii) C1to 6 alkoxy; or iii) an aromatic ring selected from phenyl, furyl orthienyl; said aromatic ring being optionally further substituted byhalogen, C1 to 6 alkyl or C1 to 6 alkoxy; R³ represents hydrogen or C1to 6 alkyl; R⁴ represents halogen, C1 to 6 alkyl substituted by one ormore halogen atoms, C1 to 6 alkoxy or C1 to 6 thioalkoxy; said alkoxy orthioalkoxy group being optionally further substituted by halogen or OH;and pharmaceutically acceptable salts thereof.
 12. A compound accordingto claim 11 wherein X represents S and Y represents O.
 13. A compoundaccording to claim 11 wherein R³ represents H.
 14. A compound accordingto claim 11 wherein R² represents optionally substituted C1 to 6 alkyl.15. A compound of formula (Ia) or (Ib), according to claim 11, or apharmaceutically acceptable salt thereof, for use as a medicament.
 16. Apharmaceutical composition comprising a compound of formula (Ia) or (Ib)according to claim 11, or a pharmaceutically acceptable salt thereof,optionally in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier.
 17. A method of treating, or reducing the risk of,diseases or conditions in which inhibition of the enzyme MPO isbeneficial which comprises administering to a person suffering from orat risk of, said disease or condition, a therapeutically effectiveamount of a compound of formula (Ia) or (Ib), as defined in claim 11 ora pharmaceutically acceptable salt thereof.
 18. The use of a compound offormula (Ia) or (Ib) as defined in claim 11 or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament, for thetreatment or prophylaxis of diseases or conditions in which inhibitionof the enzyme MPO is beneficial.
 19. The use of a compound of formula(Ia) or (Ib) as defined in claim 11 or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament, for the treatment orprophylaxis of neuroinflammatory disorders.
 20. A process for thepreparation of a compound of formula (Ia) or (Ib), as defined in claim11 or a pharmaceutically acceptable salt, enantiomer, diastereomer orracemate thereof, wherein the process comprises: (a) reaction of acompound of formula (IIa) or (IIb)

wherein R¹, R², R³ and R⁴ are as defined in formula (Ia) or (Ib), Xrepresents O or S and Y represents O; with a sulphurising compound suchas Lawesson's reagent or phosphorus pentasulphide; to give acorresponding compound wherein Y represents S; or (b) reaction of adiamine of formula (IIIa) or (IIIb)

wherein R¹, R², R³, X and Y are as defined in formula (Ia) or (Ib); witha trialkylorthoester or with an alpha-halo-substituted carboxylic acidor anhydride; and where necessary converting the resultant compound offormula (Ia) or (Ib), or another salt thereof, into a pharmaceuticallyacceptable salt thereof; or converting the resultant compound of formula(Ia) or (Ib) into a further compound of formula (Ia) or (Ib); and wheredesired converting the resultant compound of formula (Ia) or (Ib) intoan optical isomer thereof.